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Microbe-host interactions

Nov 15, 2006

Ch. 21

Science 307:1915-20, 2005.

Antimicrobial drug resistance

• Acquired ability to resist effects of achemotherapeutic to which it is normally susceptible

• Common mechanisms 1. Lack structure drug targets 2. May be impermeable to drug 3. Organism may be able to modify drug to an inactive

form 4. Organism may modify the target itself 5. Organism may develop a new pathway 6. Organism may be able to pump out the drug

R factors

• Most drug resistant bacteria isolated frompatients contain drug resistance genes onplasmids

• Many of these plasmids encode enzymes that inactivate drugs

• Multi-drug resistance plasmids predatemedical use of antibiotics

• Widespread emergence of multi-drugresistance

Resistance to all known drugs…

1950

Staphylococcus aureus

1960

Other gram-negative rods

1970 1980 1990 2000 2010

Shigella sp.

Shigella dysenteriae

Salmonella sp.

Pseudomonas aeruginosa

Neisseria gonorrhoeae Haemophilus influenzae

Salmonella typhi Haemophilus ducreyi

Streptococcus pneumoniae Enterococcus faecalis

Acinetobacter sp.

Mycobacterium tuberculosis Gram-negative Gram-positive Gram-positive/acid-fast

• Methicillin- resistant Staphylococcus aureus (MRSA)

• Vancomycin-resistant Enterococcus (VRE)

Figure by MIT OCW.

Healthcare-associated infections

• Healthcare-associated infections (HAIs) are infections that patients acquire during the course of receiving treatment for other conditions

• In hospitals alone, HAIs account for an estimated 2 million infections, 90,000 deaths, and $4.5 billion in excess health care costs annually

http://www.cdc.gov/ncidod/dhqp/healthDis.html

http://www.cdc.gov/ncidod/dhqp/healthDis.html

Changing patterns for HAIs

• 1950s to 1960s gram positive bacteria were a major problem (Streptococcus pyogenes and Staphylococcus aureus)

• 1970s and 1980s gram negative bacteriabecame a major problem (E. coli and Pseudomonas spp.)

• Currently, gram positive bacteria are againemerging as a major problem (S. aureus and Enterococcus spp.)

Methicillin-resistant Staphylococcus aureus N315

Image removed due to copyright restrictions.

Hiramatsu et al. Trends Microbiol 9:486, 2001

Terminology

• Normal microbial “flora” or “microflora” – Better term is microbiota – Commensal (at the same table)

• Pathogen – Infection versus disease

• Virulence • Opportunistic pathogen

Indigenous microbiota

• Microorganisms that inhabit body sites in which surfaces and cavities are open to the environment

• Skin, oral cavity, upper respiratory tract, gastrointestinal (GI) tract, and vagina

• Each habitat can be considered a separate ecosystem

• For every cell in human body (1013) there are 10 viable indigenous bacteria in the GI tract

• The GI tract (1014) harbors 100-fold more bacteria than the skin (1012)

Major bacteria present

Anus

Esophagus Organ Major physiological Esophagus processess Prevotella

StreptococcusVeillonella

Stomach Secretion of acid (HCI)Helicobacter Digestion of macromolecules

pH 2 Duodenum

Enterococci Lactobacilli Small Continued digestionJejumum

intestine Absorption of monosaccharides,Bacteroides amino acids, fatty acids, waterBifidobacterium

IleumClostridium pH 4-5Enterobacteria Enterococcus Escherichia Large Absoption of bile acids,ColonEubacterium intestine vitamin B12Klebsiella pH 7Lactobacillus PeptococcusPeptostreptococcusProteus Ruminococcus StaphylococcusStreptococcus

Figure by MIT OCW.

Defining the GI microbiota

• Autochthonous microbiota – Present during the evolution of an animal and

therefore present in every member of a species • Normal microbiota

– Common and perhaps even present in everyindividual in a given geographic area/community,but not in every member of the species

• True pathogens – Acquired accidentally and therefore not

normally present in all members of a communityof an animal species

Dubos et al. J Exp Med 122:67-76, 1965

Ecological principles

• In a stable GI ecosystem, all available habitats are occupied by indigenous microbiota

• Transient species derived from food, water, or even another part of the GI tract or the skin will not establish (colonize)

• Habitats are physical spaces in the GI tract normally occupied by a climax community of indigenous microbiota

• Population levels and species composition are stable and not easily disrupted

Succession & climax populations

• Lactic acid bacteria and coliforms predominate in infant human and animal GI tracts

• During weaning the microbiota changes drastically and obligate anaerobic bacteria become predominant

• The indigenous GI microbiota of adults consists of climax communities that are remarkably stable

• Each region of the GI tract has a characteristic population of microbes, in terms of complexity and population density

Model systems

• Germ free animals • Delivered by Cesarean section into sterile plastic-

film isolators • Maintained free of all bacteria, fungi, protozoa,

viruses, and other detectible life forms • Introducing microorganisms is called association

or colonization • Contamination is accidental introduction of

unwanted microorganisms • Germ free animals can be monoassociated with a

singe species or poly associated with multiplespecies

16

17

Small intestine

Esophagus

Stomach

Large intestine

Cecum

2

3

4 5

67

8

8

9

10 11

12

13

14

15

18

19

20

1

16

17

Figures by MIT OCW.

ASF 361

ASF 360

ASF 500

ASF 356

ASF 502

ASF 492

ASF 457

ASF 519

Lactobacillus animalisLactobacillus murinus

Lactobacillus mali

Lactobacillus acidophilus

Clostridium propionicumClostridium neopropionicum

Clostridium piliformeRuminococcus gnavusEubacterium contortum

Roseburia cecicola

Catonella morbiAcetitomaculum ruminis

Eubacterium plexicaudatumJohnsonella ignava

Flexistipes sinusarabicDeferribacter thermophilus

Geovibrio ferrireducensColobus Monkey sp.

Rodent sp. 1Rodent sp. 2Rodent sp. 3

(Bacteroides) merdae(Bacteroides) distasonis

(Bacteroides) forsythusCDC DF-3

Lactobacillus lactis

Lactobacillus salivarius

(% Difference)

Figure by MIT OCW.

Cp

of t

arge

t ge

ne/g

1.E+111.E+101.E+091.E+081.E+071.E+061.E+051.E+04

Gut regionE1 S1 S2 I1 I2 I3 I4 I5 I6 C1 C2 L1 L2 L3

ASF361 : spatial distribution

Cp

of t

arge

t ge

ne/g

1.E+111.E+101.E+091.E+081.E+071.E+061.E+051.E+04



123

123

Cp

of t

arge

t ge

ne/g

1.E+111.E+101.E+091.E+081.E+071.E+061.E+051.E+04



123

Continued...

Figure by MIT OCW.

Cp

of t

arge

t ge

ne/g

1.E+111.E+101.E+091.E+081.E+071.E+061.E+051.E+04



123

Cp

of ta

rget

gen

e/g

1.E+10

1.E+08

1.E+06

1.E+04

1.E+02



123

Cp

of t

arge

t ge

ne/g

1.E+111.E+101.E+091.E+081.E+071.E+061.E+051.E+04



123

Human colonic microbiota

• Highest cell densities recorded for any ecosystem • Diversity at the division level is among the lowest • Only 8 of the 55 known bacterial divisions have

been identified in colonic bacteria to date • 2 division dominate • Cytophaga-Flavobacterium-Bacteroides (CFB) • Firmicutes (genera Clostridium and Eubacterium) • Proteobacteria are common, but not dominant • Compare to many soil communities, where ≥ 20

bacterial division can be present

Bäckhed et al. Science 307:1915-19, 2005 Figure by MIT OCW.

Firmicutes

OD1

Actino

bacte

ria

Proteobacteria

ABY1

OP9

SR1

WS6

SC3WS5Termite Group 1

TM7BD1-5

Coprothermobacter

Dictyoglomus OP1

OP 11

Synergisters

Guaymas1

0.05

SC4

to the Archaea

EM3

TM6

KSB1

OP3

WS2

WS3BRC1

SBR1093NKB19

OP5Fusobacteri

a

Spiro

chae

ates

Fibr

obac

tere

s

Cya

noba

cter

iaG

reen

Non

Sul

fur

Deinococcus-Thermus

OS-K

OP8

Acidobacteria

Plantomycetales

Chlamiydiae

CFB

Chlorobi

Nitrospira Verrucomicrobi

VadinBE9 7

Marine Group ANC10

Gemm

atimonadetes

Deferribacter

Aquifacae

Desulfo

bacte

ria

OP10Thermotogae

Thermodesulfobacteria

Diversity

• > 200,000 16S rRNA sequence in GenBank

• 1,822 from human gut

• 1,689 are uncultured

• Look at 495 with length > 900 bp

• ~ 800 species • > 7,000 strains 1

80 85

16S rRNA Sequence Identity (%)

90 95 100

10

Num

ber

of T

axon

omic

Uni

ts

100

1000

Strain

Species Genus

104

Figure by MIT OCW.

Bäckhed et al. Science 307:1915-19, 2005

Helicobacter pylori

Photographs of Barry J. Marshall and J. Robin Warren removed due to copyright restrictions.Marshall and Warren won the 2005 Nobel prize in medicine for their discovery of Helicobacter pylori and its role in gastritis and peptic ulcer disease.

HP

HP+

Gastric Ulcer

1% p.a. Duodenal

Ulcer

Gastric Cancer

Gastric Lymphoma

Figure by MIT OCW.

Incidence diagram of Helicobacter pylori disease in the world today

Gastritis and peptic ulcer

Figure by MIT OCW.

http://www.cdc.gov/ulcer/

The proteins encoded by these genes assembleto form a complex type IV secretion apparatuscapable of delivering CagA from the bacterium into host cells

Growth factor-like response in host cell,cytoskeletal rearrangements

Binding to and activation of cellularphosphatase SHP-2

Phosphorylation of CagA by host-cellkinases c-Src and Lyn

Translocation of CagA into gastricepithelial cells

HP0524(VirD4)

HP0525(VirB11)

HP0528(VirB9)

HP0527(VirB10)

HP0544(VirB4) cagA

H. pylori strain 26695 genome (1,667,867 bp)

cag pathogenicity island (37,000 bp)

http://www.cdc.gov/ulcer/

H. pylori and gastritis

Images of Helicobacter pylori removed due to copyright restrictions.

Suerbaum & Michetti N Eng J Med 2002Helicobacter pylori on gastric epithelial

cells (false-color SEM)

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